© 2018 International Endodontic Journal. Published by John Wiley & Sons LtdAim: To evaluate the effectiveness of NaOCl, NaOCl-EDTA and NaOCl + HEBP activated by ultrasonics and XP-endo Finisher on organic tissue removal from simulated internal root resorption cavities. Methodology: The root canals of 144 single-rooted teeth were instrumented. The teeth were split longitudinally, and semicircular cavities were prepared in the canal walls on each half of the roots. Samples obtained from ground bovine muscle tissue were weighed and adapted into the semicircular cavities. The root fragments were reassembled and cemented to create a circular simulated resorption cavity within the canal. Teeth were divided into twelve groups (n = 12) according to the irrigation protocols: group 1: NaOCl, no activation; group 2: NaOCl, passive ultrasonic irrigation (PUI); group 3: NaOCl, XP-endo Finisher; group 4: NaOCl-EDTA, no activation; group 5: NaOCl-EDTA, PUI; group 6: NaOCl-EDTA, XP-endo Finisher; group 7: NaOCl + HEBP, no activation; group 8: NaOCl + HEBP, PUI; group 9: NaOCl + HEBP, XP-endo Finisher; group 10: distilled water, no activation; group 11: distilled water, PUI; and group 12: distilled water, XP-endo Finisher. The teeth were disassembled, and the tissue remaining inside the resorption cavities were weighed. The data were analysed statistically using two-way anova and Fisher's LSD tests with a significance level of 0.05. Results: The use of XP-endo Finisher with the experimental solutions resulted in the greatest tissue weight loss compared to the other activation protocols (P < 0.001). There was no significant difference between NaOCl and NaOCl + HEBP in terms of tissue removal. Conclusion: The use of a NaOCl + HEBP mixture activated with XP-endo Finisher was an effective irrigation regimen for removing simulated organic tissues from artificial internal root resorption cavities in the straight root canals of single-rooted teeth.